Ubiquitin ligase Fbw7 restricts the replication of hepatitis C virus by targeting NS5B for ubiquitination and degradation

Biochemical and Biophysical Research Communications
Jun ChenDeyin Guo

Abstract

The nonstructural protein 5B (NS5B) of hepatitis C virus (HCV) is an RNA-dependent RNA polymerase (RdRp) and responsible for replicating the whole HCV genome with help of viral and cellular proteins. However, how cellular factors influence NS5B and, in turn, regulating HCV replication are still poorly defined. The well known tumor suppressor Fbw7, a component of E3 ubiquitin ligase SCF(Fbw7), targets oncoproteins or cellular regulatory proteins for ubiquitin-mediated degradation through a highly conserved binding site called a Cdc4 phosphodegron (CPD). But little is known about whether Fbw7 plays a role in regulation of viral proteins. In this study, we revealed that the conserved CPD is shared by NS5B of almost all genotype of HCV and our data demonstrated that NS5B is a bona fide substrate of Fbw7. Forced expression of Fbw7 promoted the ubiquination of NS5B and negatively regulated its turnover in the proteasome-dependent manner. We further revealed the interaction between NS5B and Fbw7, which resulted in the relocation of Fbw7 from nucleus to cytoplasm. During HCV replication, ectopic expression of Fbw7 could strongly down-regulate NS5B level and consequently inhibited the virus replication. When endogenous Fbw7 was knocked ...Continue Reading

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Citations

Mar 29, 2018·Journal of Experimental & Clinical Cancer Research : CR·Yen-Hsiu YehTsai-Kun Li
Feb 16, 2020·The Journal of Infectious Diseases·Jennifer Alvarez OrellanaPatrick S Moore
May 4, 2017·Proceedings of the National Academy of Sciences of the United States of America·Hyun Jin KwunPatrick S Moore

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